Jaguar Gene Therapy Announces Successful Completion of Dosing of First Patient Cohort in Clinical Trial Evaluating JAG201 for the Treatment of a Leading Monogenic Cause of Autism Spectrum Disorder Known as Phelan-McDermid Syndrome

• Dosing of Cohort 1 complete with first three patients having received starting dose of JAG201 delivered via intracerebroventricular (ICV) injection
• First two patients in dose-escalation Cohort 2 have been dosed, and company anticipates target enrollment and dosing to be completed in Cohort 2 in Q2 2026
• No treatment-related serious adverse events (SAEs) or dose-limiting toxicities (DLTs) have been reported to date
• Early indications of clinical benefit observed in neurodevelopmental domains, including communicative, motor, cognitive and social
• There are currently no treatments for the >45,000 individuals in the U.S. with SHANK3 haploinsufficiency, a leading monogenic cause of autism that is clinically diagnosed as Phelan-McDermid syndrome

LAKE FOREST, Ill.--(BUSINESS WIRE)--Jaguar Gene Therapy, LLC (“Jaguar”) a clinical-stage biotechnology company accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases including those that impact sizeable patient populations, today announced completion of dosing of Cohort 1 in its first-in-human clinical trial evaluating the safety, tolerability and clinical activity of JAG201 in patients with SHANK3 haploinsufficiency, a leading monogenic cause of autism spectrum disorder that is clinically diagnosed as Phelan-McDermid syndrome. The first two patients in dose-escalation Cohort 2 have been dosed, and Jaguar anticipates target enrollment and dosing to be completed in Cohort 2 in Q2 2026. No treatment-related serious adverse events (SAEs) or dose-limiting toxicities (DLTs) have been reported in the trial to date. Early indications of clinical benefit have been observed across neurodevelopmental domains, including communicative, motor, cognitive and social.

“Having dosed the first five patients with JAG201 is a significant milestone for our company and most importantly, the Phelan-McDermid syndrome community as this is the first gene therapy to be clinically evaluated for treating SHANK3 haploinsufficiency, a leading monogenic cause of autism,” said Joe Nolan, CEO of Jaguar Gene Therapy. “We are pleased with the positive emerging safety profile with no treatment-related serious adverse events or dose-limiting toxicities, and with the early indications of clinical benefit that have been observed across neurodevelopmental domains, including communicative, motor, cognitive and social. We are grateful for our continued partnerships with leading clinicians and advocacy organizations to bring forward a potentially transformative gene therapy treatment option for a devastating disease with such high unmet need.”

“The successful dosing of the first five patients in the trial is exciting, and I look forward to evaluating the cumulative data for trial participants in the months ahead,” said Alexander Kolevzon, M.D., principal investigator and professor of Psychiatry and Pediatrics at the Icahn School of Medicine at Mount Sinai. “Having spent years working closely with Phelan-McDermid syndrome patients and their families in my clinical practice, I am excited to be a part of the clinical evaluation of JAG201 in an effort to potentially realize the hope for a transformational treatment option for such a devastating disease.”

JAG201 is a gene replacement therapy delivered via an adeno-associated virus serotype 9 (AAV9) vector that delivers a functional SHANK3 minigene to target neurons in the central nervous system. The therapy is administered via a one-time unilateral intracerebroventricular (ICV) injection, targeting neurons across the brain. JAG201 is designed to transduce haploinsufficient neurons to provide proper SHANK3 levels and to durably restore the synaptic function required for learning and memory, which underlie appropriate neurodevelopment and maintenance of communicative, motor, cognitive and social skills. The program is exclusively licensed from Broad Institute of MIT and Harvard.

The first-in-human clinical trial for JAG201 is a multi-center, open-label, dose-escalation study to evaluate the safety, tolerability and clinical activity of a single dose of JAG201. The trial is being conducted at the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai in New York City, at Rush University in Chicago and at Boston Children’s Hospital in Boston with plans to expand to additional sites in the future.

“While we are early in our clinical development journey, we are encouraged by the initial indications of benefit we’ve observed for JAG201 across several neurodevelopmental domains that are specifically relevant in Phelan-McDermid syndrome,” said Daniel Gallo, Ph.D., executive vice president of Clinical Development and Medical Affairs. “Jaguar is dedicated to advancing this program for the community of more than 45,000 patients who present with lifelong and severe impairments to almost all activities of daily living, characterized by delayed or absent developmental milestones and requiring 24-hour care. We look forward to presenting the first clinical data from the JAG201 first-in-human trial in the coming months.”

“Phelan-McDermid syndrome is a rare genetic neurodevelopmental disorder that results in a range of challenging clinical manifestations, including global developmental delay, impaired speech and communication, and moderate to severe disability in cognitive, social and motor functions,” said Elizabeth Berry-Kravis, M.D., Ph.D., principal investigator and neurologist at Rush University. “I see first-hand how patients and families struggle with the complex and often devastating challenges of the condition, and I am encouraged based on the positive emerging safety profile and initial indications of potential clinical benefit that JAG201 could be the first gene therapy treatment option for those living with Phelan-McDermid syndrome.”

Jaguar acknowledges patient advocacy partners Phelan-McDermid Syndrome Foundation and CureSHANK for their support in bringing the JAG201 program to the clinical phase. “The Phelan-McDermid syndrome community is encouraged by this progress, as families continue to look toward safe and effective treatment options for the many daily challenges affected by the disorder,” said Robbie Baker, CEO of the Phelan-McDermid Syndrome Foundation. “After years with few therapeutic possibilities in sight, growing momentum in research gives our community renewed hope that future therapies, including investigational approaches like JAG201, may one day help lessen the impact of Phelan-McDermid syndrome and improve quality of life for individuals and families.”

“Having the first five individuals dosed in the first gene therapy trial targeting Phelan-McDermid syndrome is a remarkable inflection point for our community and for me personally as a parent of a young adult with Phelan-McDermid syndrome who faces nearly insurmountable challenges daily,” said Geraldine Bliss, founder and president of CureSHANK. “Currently, there is a complete lack of treatment options to help our children with Phelan-McDermid syndrome, and they deserve better. We are very encouraged by the progress of the JAG201 program to date and look forward to the day when a transformative therapy will be available.”

JAG201 regulatory status

The U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease designation for JAG201. The designation is granted for products that treat serious and life-threatening rare pediatric diseases. Under this program, companies are eligible to receive a priority review voucher for a subsequent marketing application for a different product following approval of a product with Rare Pediatric Disease designation.

The FDA has also granted Fast Track designation for JAG201 based on the potential for the therapy to address a high unmet medical need for patients living with SHANK3 haploinsufficiency, which is clinically diagnosed as Phelan-McDermid syndrome. Currently, there are no therapeutic treatments approved for SHANK3 haploinsufficiency. Fast Track status allows for enhanced communication and collaboration between the FDA and drug developers, potentially accelerating the delivery of treatments to patients.

Most recently, the FDA has granted Orphan Drug designation to JAG201. The Orphan Drug designation is for therapies that show promise in the treatment, prevention or diagnosis of orphan diseases. An orphan disease is a rare disease or condition that affects fewer than 200,000 people in the United States.

About SHANK3 haploinsufficiency in ASD and Phelan-McDermid syndrome

SHANK3 haploinsufficiency is a leading monogenic cause of ASD that is clinically diagnosed as Phelan-McDermid syndrome.^1,2,5 SHANK3 haploinsufficiency occurs when one copy of a gene is deleted or contains a pathogenic variant and the remaining copy cannot produce enough protein to support healthy brain function.⁶ The SHANK3 protein is essential for building and maintaining connections between neurons, which is required for learning and development.⁶ SHANK3 haploinsufficiency is a result of pathogenic variants in SHANK3 or by chromosome 22q13.3 deletions encompassing the SHANK3 gene.^5,6,7,8

Genetic sequencing studies indicate SHANK3 pathogenic variants may be present in approximately 0.5%-0.69% of individuals with ASD, with the prevalence of Phelan-McDermid syndrome in the U.S. estimated to be more than 45,000 patients.^1,2,3,4 Individuals with Phelan-McDermid syndrome present with lifelong and severe neurobehavioral, communicative, motor, cognitive and social impairments characterized by delayed or absent developmental milestones.^5,6,8,9 Almost all activities of daily living, including being able to communicate their needs, ability to self-care, including dressing, bathing and toileting, and socialization with family or peers are absent or severely impaired, requiring 24-hour care and/or supervision.¹⁰ Additional features of Phelan-McDermid syndrome include neonatal hypotonia (low muscle tone), seizures, impaired sleep and gastrointestinal problems.^5,6

There is an overwhelming unmet need in Phelan-McDermid syndrome with no effective or approved medications that treat the underlying disease. Available treatments only address individual symptoms. Standard-of-care includes early initiation of speech, occupational, physical and behavioral therapies.^5,6,7 A majority of caregivers report that their loved ones’ treatment interventions worked “very little” or “somewhat” to address the most significant symptoms of Phelan-McDermid syndrome.¹⁰

About Jaguar Gene Therapy

Jaguar is a clinical-stage biotechnology company dedicated to accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases including those that impact sizeable patient populations. The company is made up of a proven team of experts who have first-hand experience in bringing novel gene therapy treatments to patients and their families. Jaguar is rapidly advancing an initial pipeline of three programs. The lead program targets SHANK3 haploinsufficiency, a leading monogenic cause of autism spectrum disorder that is clinically diagnosed as Phelan-McDermid syndrome. Individuals with Phelan-McDermid syndrome present with lifelong and severe neurobehavioral, communicative, motor, cognitive and social impairments characterized by delayed or absent developmental milestones. A clinical trial in pediatric patients is currently underway. The second pipeline program targets Type 1 galactosemia and the third targets Type 1 diabetes. Jaguar’s key investors include Deerfield Management Company, Eli Lilly and Company, ARCH Venture Partners and Goldman Sachs. For more information, please visit www.jaguargenetherapy.com and follow Jaguar Gene Therapy on LinkedIn.

References

1. Betancur C, Buxbaum JD. SHANK3 haploinsufficiency: a "common" but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mol Autism. 2013;4(1):17. Published 2013 Jun 11. doi:10.1186/2040-2392-4-17
2. Leblond CS, Nava C, Polge A, et al. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10(9):e1004580. Published 2014 Sep 4. doi:10.1371/journal.pgen.1004580
3. https://www.census.gov/popclock
4. https://www.cdc.gov/autism/data-research/index.html
5. Kolevzon A, Angarita B, Bush L, et al. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. J Neurodev Disord. 2014;6(1):39. doi:10.1186/1866-1955-6-39
6. Costales JL, Kolevzon A. Phelan-McDermid Syndrome and SHANK3: Implications for Treatment. Neurotherapeutics. 2015;12(3):620-630. doi:10.1007/s13311-015-0352-z
7. Srivastava S, Sahin M, Buxbaum JD, et al. Updated consensus guidelines on the management of Phelan-McDermid syndrome. Am J Med Genet A. 2023;191(8):2015-2044. doi:10.1002/ajmg.a.63312
8. Levy T, Foss-Feig JH, Betancur C, et al. Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium. Hum Mol Genet. 2022;31(4):625-637. doi:10.1093/hmg/ddab280
9. Farmer C, Giserman-Kiss I, Mohanty E, et al. Retrospective Reports of Skill Attainment and Loss in Phelan-McDermid Syndrome. Am J Intellect Dev Disabil. 2025;130(5):362-379. doi:10.1352/1944-7558-130.5.362
10. Externally-Led Patient-Focused Drug Development (EL-PFDD) for Phelan-McDermid Syndrome (PMS). Hosted by CureSHANK and Phelan-McDermid Syndrome Foundation. 8 November 2022. Voice of the Patient Report (VOPR). Available at: https://www.cureshank.org/elpfdd-meeting

Disclosure
Dr. Alexander Kolevzon has served as a paid consultant for Jaguar Gene Therapy.
Dr. Elizabeth Berry-Kravis has served as a paid consultant for Jaguar Gene Therapy.

Kate Neer
media@jaguargenetherapy.com
(815) 978-3891